raltitrexed

Raltitrexed
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of; administration	Intravenous
ATC code	L01BA03 (WHO)
Legal status
Legal status	UK: POM (Prescription only); Not available in U.S.;
Identifiers
	IUPAC name N-[(5-{methyl[(2-methyl-4-oxo-1,4-dihydroquinazolin-6-yl)methyl]amino}-2-thienyl)carbonyl]-L-glutamic acid;
CAS Number	112887-68-0
PubChem (CID)	104758
IUPHAR/BPS	7403
DrugBank	DB00293
ChemSpider	94568
UNII	FCB9EGG971
KEGG	D01064
ChEMBL	CHEMBL225071
PDB ligand ID	D16 (PDBe, RCSB PDB)
ECHA InfoCard	100.180.242
Chemical and physical data
Formula	C21H22N4O6S
Molar mass	458.489 g/mol
3D model (Jmol)	Interactive image
	SMILES O=C(c3sc(N(C)Cc2cc1C(=O)\N=C(/Nc1cc2)C)cc3)N[C@H](C(=O)O)CCC(=O)O ;
	InChI InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1 ; Key:IVTVGDXNLFLDRM-HNNXBMFYSA-N ;
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Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/01/27 07:34:14」(JST)

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[Wiki en表示]

Raltitrexed (Tomudex, TDX, ZD 1694) is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca.^[1]

Uses

Used in treatment of colorectal cancer since 1998. It may also be used in the treatment of malignant mesothelioma.^[2]

Mechanism of action

Raltitrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites, which inhibit one or more of three enzymes that use folate and derivatives as substrates: DHFR, GARFT and thymidylate synthase. Raltitrexed is fully active after polyglutamylation, which allows cellular retention of the drug.

By inhibiting Thymidylate synthase (TS), thus formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.

Inhibition of L1210 cell growth in culture IC₅₀ = 9 nM, is one of the strongest antimetabolites in use.

Structure and phase I clinical trial of the precursor drug, CB3717, was described in 1986.^[3]

References

^ Widemann BC, Balis FM, Godwin KS, McCully C, Adamson PC (1999). "The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model". Cancer Chemother. Pharmacol. 44 (6): 439–43. doi:10.1007/s002800051116. PMID 10550563.
^ Zuidema PJ. "[Primary amebic meningoencephalitis]". Ned Tijdschr Geneeskd. 120: 477. PMID 1256598.
^ Calvert AH, Alison DL, Harland SJ, et al. (August 1986). "A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717". J. Clin. Oncol. 4 (8): 1245–52. PMID 3734849.

UpToDate Contents

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1. Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials
2. Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management
3. 進行性膵外分泌癌に対する化学療法 chemotherapy for advanced exocrine pancreatic cancer
4. 切除不能悪性胸膜中皮腫に対する全身療法 systemic treatment for unresectable malignant pleural mesothelioma
5. 抗腫瘍療法関連肺毒性：細胞傷害性薬物 pulmonary toxicity associated with antineoplastic therapy cytotoxic agents

English Journal

Nucleoside Analogue-Based Supramolecular Nanodrugs Driven by Molecular Recognition for Synergistic Cancer Therapy.

Wang D1, Yu C1, Xu L1, Shi L1, Tong G1, Wu J1, Liu H2, Yan D1, Zhu X1.
Journal of the American Chemical Society.J Am Chem Soc.2018 Jul 18;140(28):8797-8806. doi: 10.1021/jacs.8b04556. Epub 2018 Jul 10.
PMID 29940110

[Fluoropyrimidines cardiac toxicity: 5-fluorouracil, capecitabine, compound S-1 and trifluridine/tipiracil].

Vaflard P1, Ederhy S2, Torregrosa C3, André T4, Cohen R4, Lopez-Trabada D5.
Bulletin du cancer.Bull Cancer.2018 Jun 27. pii: S0007-4551(18)30171-1. doi: 10.1016/j.bulcan.2018.05.005. [Epub ahead of print]
PMID 29960638

Transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed for hepatocellular carcinoma with major portal vein tumor thrombus.

Zhu LZ1, Xu S2, Qian HL3.
World journal of gastroenterology.World J Gastroenterol.2018 Jun 21;24(23):2501-2507. doi: 10.3748/wjg.v24.i23.2501.
PMID 29930471

Japanese Journal

Determination of raltitrexed in human plasma by high performance liquid chromatography-electrospray ionization-mass spectrometry

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 853(1), 147-153, 2007-06-15
NAID 10025803842

悪性胸膜中皮腫に対する化学療法 (特集:中皮腫トピックス)

日本胸部臨床 65(7), 640-645, 2006-07
NAID 40007376288

Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma : an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada

J Clin Oncol. 23, 6881-6889, 2005
NAID 30022792945

Related Pictures

[1] Widemann BC, Balis FM, Godwin KS, McCully C, Adamson PC (1999). "The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model". Cancer Chemother. Pharmacol. 44 (6): 439–43. doi:10.1007/s002800051116. PMID 10550563.

[raltitrexed-2] Zuidema PJ. "[Primary amebic meningoencephalitis]". Ned Tijdschr Geneeskd. 120: 477. PMID 1256598.

[3] Calvert AH, Alison DL, Harland SJ, et al. (August 1986). "A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717". J. Clin. Oncol. 4 (8): 1245–52. PMID 3734849.

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